Regenerative medicine is one of the great biomedical challenges of this century, seeking to regenerate parts of the human body throughout life lost to trauma, disease, or genetic factors. Real progress will hinge on our ability to combine effectively the frontiers of technology, biology, and clinical medicine to develop regenerative strategies. This Bioengineering Research Partnership (BRP), proposed by a team of seven investigators in the fields of neurology, surgery, endocrinology, materials science, chemistry, biomedical engineering, and chemical engineering, focuses on two specific challenges of great clinical importance, regeneration of the central nervous system (CNS) and cell replacement therapies for diabetic patients. In this application the target of the team is to develop multiple scaffold technologies and use CNS regeneration and pancreatic tissue replacement as their testing ground. The CNS targets include injection of self-assembling molecules and genetically engineered stem cells into the injured spinal cord or brain following stroke, and the diabetes targets include the development of a subcutaneous islet transplant. The four basic technologies are self-assembling nanofibers customizable to bear multiple tissue specific biological epitopes or have programmable delivery of growth factors; microporous biodegradable scaffolds that deliver genes or growth factors and guide cell migration; post-translationally modified recombinant polypeptides with customizable architecture and bioactivity; and enzyme-driven liquid-to-solid transitions of soluble bioactive peptides. The integrated scaffold technologies proposed include, the use of self-assembling nanofiber technology to modify microporous materials and create micro-nano hierarchical scaffolds, the adaptation of recombinant polypeptides for in situ enzyme driven solidification, and the development of bioactive two-phase molecular composite scaffolds containing linear polypeptides and peptide nanostructures.